b'BLEED: 8.375"w TRIM: 7.875"w SAFETY: 6.875"w CABOMETYXEverolimus CABOSUNCABOMETYX Sunitinib(n=331)1 (n=322) The safety of CABOMETYX was evaluated in CABOSUN, aAdverse Reaction (n = 78) (n = 72)Adverse Reaction randomized, open-label trial in patients with advanced renal cellGrade 3-4 1 Grade 3-4 1CODE_CABOMETYX_RCC_3PG_Efficacy In Balance JournalAd_7.875" x 10.5_A-Size_Page All 2 GradeAll2 Gradecarcinoma, in which 78 patients received CABOMETYX 60 mg onceSAFETY: 9.5"hTRIM: 10.5"hBLEED: 11.25"h Grades 3-4 Grades 3-4 daily and 72 patients received sunitinib 50 mg once daily (4 weeksPercentage (%) of PatientsPercentage (%) of Patients on treatment followed by 2 weeks off), until disease progression orRenal and UrinaryMetabolism andunacceptable toxicity. The median duration of treatment was 6.5Renal failure acute 4 1Nutrition months (range 0.228.7) for patients receiving CABOMETYXProteinuria 3 1Decreased appetite 46 3 34 1 and 3.1 months (range 0.225.5) for patients receiving sunitinib. ALT, alanine aminotransferase; AST, aspartate aminotransferase1NCI CTCAE Version 4.0Skin andWithin 30 days of treatment, there were 4 deaths in patients treated2Subcutaneous Tissue with CABOMETYX and 6 deaths in patients treated with sunitinib. Laboratory abnormalities are reported as adverse reactions and notPalmar-plantarOf the 4 patients treated with CABOMETYX, 2 patients died due to3 based on shifts in laboratory valueserythrodysesthesia 42 8 6 1 gastrointestinal perforation, 1 patient had acute renal failure, and Includes the following term: hypertensionRash 4 23 1 43 1 1 patient died due to clinical deterioration. All Grade 3-4 adverseCHECKMATE-9ER Dry skin 11 0 10 0 reactions were collected in the entire safety population. The mostThe safety of CABOMETYX with nivolumab was evaluated in Vascular frequent Grade 3-4 adverse reactions (5%) in patients treatedCHECKMATE-9ER, a randomized, open-label study in patients Hypertension 5 39 16 8 3 with CABOMETYX were hypertension, diarrhea, hyponatremia,with previously untreated advanced RCC. Patients received Investigations hypophosphatemia, PPE, fatigue, increased ALT, decreasedCABOMETYX 40 mg orally once daily with nivolumab 240 mg Weight decreased 31 2 12 0 appetite, stomatitis, pain, hypotension, and syncope.over 30 minutes every 2 weeks (n=320) or sunitinib 50 mg Nervous System The median average daily dose was 50.3 mg for CABOMETYXdaily, administered orally for 4 weeks on treatment followed Dysgeusia 24 0 9 0 and 44.7 mg for sunitinib (excluding scheduled sunitinib non- by 2 weeks off (n=320). CABOMETYX could be interrupted or Headache 11 1 12 1 dosing days). The dose was reduced in 46% of patients receivingreduced to 20 mg daily or 20 mg every other day. The median CABOMETYX and in 35% of patients receiving sunitinib. Theduration of treatment was 14 months (range: 0.2 to 27 months) in Dizziness 11 0 7 0 dose was held in 73% of patients receiving CABOMETYX and inCABOMETYX and nivolumab-treated patients. In this trial, 82% of Endocrine 71% of patients receiving sunitinib. Based on patient disposition,patients in the CABOMETYX and nivolumab arm were exposed Hypothyroidism 21 0 1 1 21% of patients receiving CABOMETYX and 22% of patientsto treatment for 6 months and 60% of patients were exposed to Respiratory, Thoracic,receiving sunitinib discontinued due to an adverse reaction.treatment for 1 year. and Mediastinal Table 3. Grade 3-4 Adverse Reactions Occurring in1%Serious adverse reactions occurred in 48% of patients receiving Dysphonia 20 1 4 0 Patients Who Received CABOMETYX in CABOSUN CABOMETYX and nivolumab. Dyspnea 19 3 29 4 The most frequent (2%) serious adverse reactions were Cough 18 1 33 1 CABOMETYX Sunitinib diarrhea, pneumonia, pneumonitis, pulmonary embolism, urinary Blood and Lymphatic Adverse Reaction (n = 78) (n = 72) tract infection, and hyponatremia. Fatal intestinal perforations Anemia 17 5 38 16 Grade 3-4 1 Grade 3-4 1 occurred in 3 (0.9%) patients. Musculoskeletal andPercentage (%) of Patients Adverse reactions leading to discontinuation of either Connective Tissue Patients with any Grade68 65 CABOMETYX or nivolumab occurred in 20% of patients: 8% Pain in extremity 14 1 8 1 3-4 Adverse Reaction CABOMETYX only, 7% nivolumab only, and 6% both drugs due Muscle spasms 13 0 5 0 to the same adverse reaction at the same time. Adverse reactions Arthralgia 11 1 14 1 Gastrointestinal leading to dose interruption or reduction of either CABOMETYX or Renal and Urinary Diarrhea 10 11 nivolumab occurred in 83% of patients: 46% CABOMETYX only, Proteinuria 12 2 9 1 Stomatitis 5 6 3% nivolumab only, and 21% both drugs due to the same adverse 1Nausea 3 4 reaction at the same time, and 6% both drugs sequentially. One subject randomized to everolimus received cabozantinib.2Vomiting 1 3 The most common adverse reactions reported in 20% of National Cancer Institute (NCI) Common Terminology Criteria forConstipation 1 0 patients treated with CABOMETYX and nivolumab were diarrhea, Adverse Events (CTCAE) Version 4.03Includes the following terms: abdominal pain, abdominal pain upper,General fatigue, hepatotoxicity, PPE, stomatitis, rash, hypertension,and abdominal pain lower Fatigue 6 17 hypothyroidism, musculoskeletal pain, decreased appetite, 4Includes the following terms: rash, rash erythematous, rash follicular,nausea, dysgeusia, abdominal pain, cough, and upper respiratory Pain 5 0rash macular, rash papular, rash pustular, rash vesicular, genitaltract infection.rash, intermittent leg rash, rash on scrotum and penis, rash maculo- Metabolism and Nutritionpapular, rash pruritic, contact dermatitis, dermatitis acneiform Hyponatremia 2 9 8 Table 4. Adverse Reactions in 15% of Patients receiving 5Includes the following terms hypertension, blood pressure increased,Hypophosphatemia 2 9 7 CABOMETYX and Nivolumab-CHECKMATE-9ER hypertensive crisis, blood pressure fluctuation Decreased appetite 5 1Dehydration 4 1 CABOMETYXSunitinib Other clinically important adverse reactions (all grades) that wereHypocalcemia 2 3 0 and Nivolumab(n=320)reported in 10% of patients treated with CABOMETYX included:Hypomagnesemia 2 3 0 Adverse Reaction (n=320)wound complications (2%), convulsion (1%), pancreatitis (1%),Hyperkalemia 2 1 3 GradesGradesGradesGrades osteonecrosis of the jaw (1%), and hepatitis cholestatic (1%). Skin and Subcutaneous1-4 3-4 1-4 3-4Table 2. Laboratory Abnormalities Occurring in25%TissuePercentage (%) of PatientsPatients Who Received CABOMETYX in METEOR Palmar-plantar8 4 Gastrointestinal erythrodysesthesia Diarrhea 64 7 47 4.4CABOMETYXEverolimus Skin ulcer 3 0 Nausea 27 0.6 31 0.3Laboratory Abnormality(n=331) (n=322) Vascular 3 Abdominal Pain a 22 1.9 15 0.3AllGradeAllGradeHypertension 28 21 Vomiting 17 1.9 21 0.3Grades 3-4 Grades 3-4 Hypotension 5 1 Dyspepsia b 15 0 22 0.3Percentage (%) of Patients Angiopathy 1 1 General Chemistry Investigations 2 Fatigue c 51 8 50 8Increased AST74 3 40 1 Increased ALT 5 0 HepatobiliaryWeight decreased 4 0 dIncreased ALT68 3 32 1 Increased AST 2 3 3 Hepatotoxicity 44 11 26 5Increased creatinine58 1 71 0 Increased blood Skin and Subcutaneous Tissue Increased53 4 73 13 creatinine 2 3 3 Palmar-plantar40 8 41 8triglyceridesLymphopenia 2 1 6 erythrodysesthesiaHypophosphatemia 48 8 36 5 Thrombocytopenia 2 1 11 Stomatitis e 37 3.4 46 4.4Hyperglycemia 37 2 59 8 Nervous System Rash f 36 3.1 14 0Hypoalbuminemia 36 2 28 1 Syncope 5 0 Pruritus 19 0.3 4.4 0Increased ALP35 2 29 1 Respiratory, Thoracic,Vascular Hypomagnesemia 31 7 4 1 and Mediastinal Hypertension g 36 13 39 14Hyponatremia 30 8 26 6 Dyspnea 1 6 Endocrine Increased GGT27 5 43 9 Dysphonia 1 0 Hypothyroidism h 34 0.3 30 0.3Hematology Blood and Lymphatic Musculoskeletal and Connective Tissue Leukopenia35 1 31 1 Anemia 1 3 Musculoskeletal pain i 33 3.8 29 3.1Neutropenia31 2 17 1 Psychiatric Arthralgia 18 0.3 9 0.3Anemia 1 31 4 71 17 Depression 4 0 Metabolism and Nutrition Lymphopenia 25 7 39 12 Confusional state 1 1 Decreased appetite 28 1.9 20 1.3InfectionsThrombocytopenia 25 1 27 1 Lung infection 4 0 Nervous System DisordersALP,alkalinephosphatase; ALT,alanineaminotransferase; AST,Musculoskeletal andDysgeusia 24 0 22 0aspartate aminotransferase; GGT, gamma glutamyl transferase.Connective Tissue Headache 16 0 12 0.6NCI CTCAE, Version 4.01Based on laboratory abnormalities Back pain 4 0 Respiratory, Thoracic, and MediastinaljBone pain 3 1 Cough 20 0.3 17 0Pain in extremity 3 0 Dysphonia 17 0.3 3.4 0Arthralgia 1 072582_CA-1121-5_Exelixis_Cabometyx_HCP-Brief_7-75x10-75_r1v1jl.indd 2 8/5/22 12:29 PM'